Sevelamer Hydrochloride

Warnings and Precautions ( 5.1 ) 04/2020

1. INDICATIONS AND USAGE Sevelamer hydrochloride tablets are indicated for the control of serum phosphorus in patients with chronic kidney disease (CKD) on dialysis. The safety and efficacy of sevelamer hydrochloride tablets in CKD patients who are not on dialysis have not been studied. • Sevelamer hydrochloride tablets are a phosphate binder indicated for the control of serum phosphorus in patients with chronic kidney disease on dialysis. ( 1 )

2 DOSAGE & ADMINISTRATION Patients Not Taking a Phosphate Binder. The recommended starting dose of sevelamer hydrochloride tablets is 800 mg to 1600 mg, which can be administered as one or two 800 mg sevelamer hydrochloride tablets or two to four 400 mg sevelamer hydrochloride tablets, with meals based on serum phosphorus level. Table 1 provides recommended starting doses of sevelamer hydrochloride tablets for patients not taking a phosphate binder. Table 1: Starting Dose for Dialysis Patients Not Taking a Phosphate Binder Serum Phosphorus Sevelamer Hydrochloride Tablets 800 mg Sevelamer Hydrochloride Tablets 400 mg Greater than 5.5 and less than 7.5 mg/dL 1 tablet three times daily with meals 2 tablets three times daily with meals Greater than or equal to 7.5 and less than 9 mg/dL 2 tablets three times daily with meals 3 tablets three times daily with meals Greater than or equal to 9 mg/dL 2 tablets three times daily with meals 4 tablets three times daily with meals Patients Switching from Calcium Acetate. In a study in 84 CKD patients on hemodialysis, a similar reduction in serum phosphorus was seen with equivalent doses (approximately mg for mg) of sevelamer hydrochloride tablets and calcium acetate. Table 2 gives recommended starting doses of sevelamer hydrochloride tablets based on a patient’s current calcium acetate dose. Table 2: Starting Dose for Dialysis Patients Switching From Calcium Acetate to Sevelamer Hydrochloride Tablets Calcium Acetate 667 mg (Tablets per meal) Sevelamer Hydrochloride Tablets 800 mg (Tablets per meal) Sevelamer Hydrochloride Tablets 400 mg (Tablets per meal) 1 tablet 1 tablet 2 tablets 2 tablets 2 tablets 3 tablets 3 tablets 3 tablets 5 tablets Dose Titration for All Patients Taking Sevelamer Hydrochloride Tablets. Adjust dosage based on the serum phosphorus concentration with a goal of lowering serum phosphorus to 5.5 mg/dL or less. Increase or decrease by one tablet per meal at two-week intervals as necessary. Table 3 gives a dose titration guideline. The average dose in a Phase 3 trial designed to lower serum phosphorus to 5 mg/dL or less was approximately three sevelamer hydrochloride 800 mg tablets per meal. The maximum average daily sevelamer hydrochloride tablets dose studied was 13 g. Table 3: Dose Titration Guideline Serum Phosphorus Sevelamer Hydrochloride Tablets Dose Greater than 5.5 mg/dL Increase 1 tablet per meal at 2-week intervals 3.5 to 5.5 mg/dL Maintain current dose Less than 3.5 mg/dL Decrease 1 tablet per meal • Starting dose is one or two 800 mg or two to four 400 mg tablets three times per day with meals. ( 2 ) • Adjust by one tablet per meal in two-week intervals as needed to obtain serum phosphorus target (3.5 to 5.5 mg/dL). ( 2 )

3. DOSAGE FORMS AND STRENGTHS 400 mg Tablets: off-white to pale yellow, oval shaped, biconvex film-coated tablets, imprinted with ‘G446’ on one side and plain on the other side. 800 mg Tablets: off-white to pale yellow, modified capsule shaped, biconvex film-coated tablets, imprinted with ‘G447’ on one side and plain on the other side. • Tablets: 800 mg and 400 mg ( 3 )

4 CONTRAINDICATIONS Sevelamer hydrochloride tablets are contraindicated in patients with bowel obstruction. Sevelamer hydrochloride tablets are contraindicated in patients with known hypersensitivity to sevelamer hydrochloride or to any of the excipients. • Bowel obstruction. ( 4 ) • Known hypersensitivity to sevelamer hydrochloride or to any of the excipients. ( 4 )

6 ADVERSE REACTIONS • The most common reasons for discontinuing treatment were gastrointestinal adverse reactions. ( 6.1 ) • In a parallel design study of 12 weeks duration, treatment-emergent adverse reactions to sevelamer hydrochloride tablets in peritoneal dialysis patients included dyspepsia (12%), peritonitis (8%), diarrhea (5%), nausea (5%), constipation (4%), pruritus (4%), abdominal distension (3%), vomiting (3%), fatigue (3%), anorexia (3%), and arthralgia (3%). ( 6.1 ) • Cases of fecal impaction and, less commonly, ileus, bowel obstruction, and bowel perforation have been reported. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharma USA, Inc. at 1-888-943-3210 or 1-855-926-3384 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In a parallel design study of sevelamer hydrochloride with treatment duration of 52 weeks, adverse reactions reported for sevelamer hydrochloride (n=99) were similar to those reported for the active-control group (n=101). Overall adverse reactions among those treated with sevelamer hydrochloride occurring in greater than 5% of patients included: vomiting (22%), nausea (20%), diarrhea (19%), dyspepsia (16%), abdominal pain (9%), flatulence (8%), and constipation (8%). A total of 27 patients treated with sevelamer and 10 patients treated with comparator withdrew from the study due to adverse reactions. Based on studies of 8 to 52 weeks, the most common reason for withdrawal from sevelamer hydrochloride was gastrointestinal adverse reactions (3% to 16%). In 143 peritoneal dialysis patients studied for 12 weeks, most adverse reactions were similar to adverse reactions observed in hemodialysis patients. The most frequently occurring treatment-emergent serious adverse reaction was peritonitis (8 reactions in 8 patients [8%] in the sevelamer group and 2 reactions in 2 patients [4%] on active control). Thirteen patients (14%) in the sevelamer group and 9 patients (20%) in the active-control group discontinued, mostly for gastrointestinal adverse reactions. Patients on peritoneal dialysis should be closely monitored to ensure the reliable use of appropriate aseptic technique with the prompt recognition and management of any signs and symptoms associated with peritonitis. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of sevelamer hydrochloride tablets: hypersensitivity, pruritus, rash, abdominal pain, bleeding gastrointestinal ulcers, colitis, ulceration, necrosis, fecal impaction and uncommon cases of ileus, intestinal obstruction, and intestinal perforation. Appropriate medical management should be given to patients who develop constipation or have worsening of existing constipation to avoid severe complications. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure.

7. DRUG INTERACTIONS There are no empirical data on avoiding drug interactions between sevelamer hydrochloride and most concomitant oral drugs. For oral medication where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy (e.g., cyclosporine, tacrolimus, levothyroxine), consider separation of the timing of the administration of the two drugs [see Clinical Pharmacology ( 12.3 )] . The duration of separation depends upon the absorption characteristics of the medication concomitantly administered, such as the time to reach peak systemic levels and whether the drug is an immediate-release or an extended-release product. Where possible monitor clinical responses or blood levels of concomitant drugs that have a narrow therapeutic range. Table 4: Sevelamer Drug Interactions Oral drugs for which sevelamer did not alter the pharmacokinetics when administered concomitantly Digoxin Enalapril Iron Metoprolol Warfarin Oral drugs that have demonstrated interaction with sevelamer and are to be dosed separately from sevelamer hydrochloride Dosing Recommendations Ciprofloxacin Take at least 2 hours before or 6 hours after sevelamer Mycophenolate mofetil Take at least 2 hours before sevelamer • When clinically significant drug interactions are expected, separate the timing of administration and monitor clinical responses or blood levels of the concomitant medication. ( 7 ) • Sevelamer did not alter the pharmacokinetics of digoxin, enalapril, iron, metoprolol, and warfarin. ( 7 ) • Sevelamer binds ciprofloxacin and mycophenolate mofetil; dose these drugs separately from sevelamer hydrochloride. ( 7 )

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Sevelamer hydrochloride is not absorbed systemically following oral administration and maternal use is not expected to result in fetal exposure to the drug. Clinical Considerations Sevelamer hydrochloride may decrease serum levels of fat soluble vitamins and folic acid in pregnant women [see Clinical Pharmacology (12.2) ] . Consider supplementing with these vitamins. Data Animal data In pregnant rats given dietary doses of 0.5, 1.5, or 4.5 g/kg/day of sevelamer hydrochloride during organogenesis, reduced or irregular ossification of fetal bones, probably due to a reduced absorption of fat-soluble vitamin D, occurred at 7 to 21 times the maximum human equivalent dose of 13 g based on 60 kg body weight. In pregnant rabbits given oral doses of 100, 500, or 1000 mg/kg/day of sevelamer hydrochloride by gavage during organogenesis, an increase of early resorptions occurred in the high-dose group (human equivalent dose approximately 5 times the maximum clinical trial dose based on 60 kg body weight). 8.2 Lactation Risk Summary Sevelamer hydrochloride is not absorbed systemically by the mother following oral administration and breastfeeding is not expected to result in exposure of the child to sevelamer hydrochloride. Clinical Considerations Sevelamer hydrochloride may decrease serum levels of fat soluble vitamins and folic acid in lactating women [see Clinical Pharmacology (12.2) ] . Consider supplementing with these vitamins. 8.4 Pediatric Use The safety and efficacy of sevelamer hydrochloride has not been established in pediatric patients. 8.5 Geriatric Use Clinical studies of sevelamer hydrochloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range.

12.1 Mechanism of Action Sevelamer hydrochloride tablets contain sevelamer hydrochloride, a non-absorbed binding crosslinked polymer. It contains multiple amines separated by one carbon from the polymer backbone. These amines exist in a protonated form in the intestine and interact with phosphate molecules through ionic and hydrogen bonding. By binding phosphate in the dietary tract and decreasing absorption, sevelamer hydrochloride lowers the phosphate concentration in the serum.

11. DESCRIPTION The active ingredient in Sevelamer Hydrochloride Tablets is sevelamer hydrochloride, a polymeric amine that binds phosphate and is meant for oral administration. Sevelamer hydrochloride is poly(allylamine hydrochloride) crosslinked with epichlorohydrin in which 40% of the amines are protonated. It is known chemically as poly(allylamine- co -N,N'-diallyl-1,3-diamino-2-hydroxypropane) hydrochloride. Sevelamer hydrochloride is hydrophilic, but insoluble in water. The structure is represented in Figure 1. Figure 1: Chemical Structure of Sevelamer Hydrochloride a, b = number of primary amine groups a + b = 9 c = number of crosslinking groups c = 1 n = fraction of protonated amines n = 0.4 m = large number to indicate extended polymer network The primary amine groups shown in the structure are derived directly from poly(allylamine hydrochloride). The crosslinking groups consist of two secondary amine groups derived from poly(allylamine hydrochloride) and one molecule of epichlorohydrin. Sevelamer Hydrochloride Tablets: Each film-coated tablet of sevelamer hydrochloride contains either 800 mg or 400 mg of sevelamer hydrochloride on an anhydrous basis. The inactive ingredients are colloidal silicon dioxide, diacetylated monoglycerides, hypromellose, lactose monohydrate, maize starch, mannitol, talc and zinc stearate. The imprinting ink for sevelamer hydrochloride tablets has the following components: black iron oxide, butyl alcohol, isopropyl alcohol, propylene glycol, ammonium hydroxide and shellac. chemical-structure

10. OVERDOSAGE Sevelamer hydrochloride has been given to normal healthy volunteers in doses of up to 14 g per day for eight days with no adverse effects. Sevelamer hydrochloride has been given in average doses up to 13 g per day to hemodialysis patients. There are no reports of overdosage with sevelamer hydrochloride in patients. Since sevelamer hydrochloride is not absorbed, the risk of systemic toxicity is low.

16. HOW SUPPLIED/STORAGE AND HANDLING Sevelamer Hydrochloride Tablets, 400 mg are supplied as off-white to pale yellow, oval shaped, biconvex film-coated tablets, imprinted with ‘G446’ on one side and plain on the other side and are supplied as follows: Bottles of 30 tablets with child-resistant closures: NDC 68462-446-30 Bottles of 360 tablets with child-resistant closures: NDC 68462-446-26 Sevelamer Hydrochloride Tablets, 800 mg are supplied as off-white to pale yellow, modified capsule shaped, biconvex film-coated tablets, imprinted with ‘G447’ on one side and plain on the other side and are supplied as follows: Bottles of 30 tablets with child-resistant closures: NDC 68462-447-30 Bottles of 180 tablets with child-resistant closures: NDC 68462-447-18 Storage: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Do not use sevelamer hydrochloride tablets after the expiration date on the bottle. Dispense in a tight container. Protect from moisture and store in a dry place. Keep tablets in original/pharmacy container.